A number of studies have found that African Americans have significantly higher prevalence and incidence of non-familial Alzheimer's Disease (AD) than Caucasians. However, because the cognitive tests used in part to diagnose AD have low specificity among African Americans, it is unclear whether misdiagnosis contributed to these findings. If rates of AD are in fact elevated, these studies suggest that different genetic or environmental factors may influence AD risk among African Americans. While the APOE D4 allele, the major genetic risk factor for AD, is more frequent among African Americans, the relative risk is somewhat lower than in other populations. It is possible that the association of APOE with AD is modified by the presence and severity of cardiovascular and cerebrovascular disease. The current proposal will address these issues by conducting a genetic association study of AD among African Americans with a carefully refined phenotype, including cognitive test performance, cardiovascular health, and brain imaging data. We propose a collaborative study to be conducted at four sites which specialize in assessment of AD and serve large populations of African Americans: Columbia University in New York City, Duke University and North Carolina A&T State University in North Carolina, and Vanderbilt University in Tennessee. We will 1) refine the phenotype of AD among African Americans by incorporating our past work on the role of cultural and educational experience on cognitive test performance in order to provide accurate diagnoses of AD, collect biomarkers related to subclinical cardiovascular disease, and obtain MRI brain images to quantify volume of white matter hyperintensities, infarct burden, and total brain; 2) we will test the association of select candidate genes in matched African American AD cases and controls, and examine the effect of cardiovascular and cerebrovascular disease as potential modifiers of risk; and 3) we will examine genotype- phenotype relations among candidate genes and several quantitative traits, including performance on measures of learning and memory, age at onset of AD, and cardiovascular and cerebrovascular disease burden. [unreadable] [unreadable] [unreadable] [unreadable]